Relationship between Me:Ca_Otolith and Me:Ca_Water for Sr (A) and Ba (B).

Lines were fitted by linear regression analysis at individual elemental concentrations. Data represent the mean values of Me:CaOtolith or Me:CaWater for each treatment.</p

Results of ANOVA to evaluate the effects of water elemental concentrations (Me:Ca_Water) on otolith elemental concentrations (Me:Ca_Otolith) for Sr and Ba.

Results of ANOVA to evaluate the effects of water elemental concentrations (Me:CaWater) on otolith elemental concentrations (Me:CaOtolith) for Sr and Ba.</p

Measured Ba concentrations (mean±SD) in water (Ba:Ca_Water, A-D) and otoliths (Ba:Ca_Otolith, E-H) across treatments (two-way ANOVA, P<0.05).

Measured Ba concentrations (mean±SD) in water (Ba:CaWater, A-D) and otoliths (Ba:CaOtolith, E-H) across treatments (two-way ANOVA, P<0.05).</p

Average daily water temperature, salinity and feeding management across treatments over the course of the experiment.

Solid line, water temperature; dotted line, water salinity.</p

Summary of Sr and Ba water concentrations, elemental errors, final total length (L_T) and otolith weight (W_O) for the fish in the experiment.

Summary of Sr and Ba water concentrations, elemental errors, final total length (LT) and otolith weight (WO) for the fish in the experiment.</p

Measured Sr concentrations (mean±SD) in water (Sr:Ca_Water, A-D) and otoliths (Sr:Ca_Otolith, E-H) across treatments (two-way ANOVA, <i>P</i><0.05).

Measured Sr concentrations (mean±SD) in water (Sr:CaWater, A-D) and otoliths (Sr:CaOtolith, E-H) across treatments (two-way ANOVA, P<0.05).</p

Plots of mean D_Me vs. ambient Me:Ca_Water for Sr (A) and Ba (B).

The lines of the best trends represent the trends at different elemental concentrations. Data represent the mean values of DMe or Me:CaWater for each treatment.</p

Additional file 1: of Complement activation contributes to perioperative neurocognitive disorders in mice

Representative images of C3/NeuN double immunostaining show no detectable C3 in hippocampal neurons on day 1. (PDF 3770 kb

DataSheet_1_Metabolomic and transcriptomic analyses reveal response mechanisms of juvenile flounder (Paralichthys olivaceus) to sublethal methylmercury.zip

Although methylmercury (MeHg) has been recognized as a typical heavy metal posing huge damages to various life processes of fish, the response mechanisms of marine fish at early life stages (ELSs) to MeHg is still poorly understood. In this study, non-targeted liquid chromatography-mass spectrometry (LC-MS) based metabolomic and transcriptomic approaches were used to explore response mechanisms of juvenile flounder (Paralichthys olivaceus) to long-term sublethal MeHg exposure (0 and 1.0 μg L-1; 30 d). After exposure, growth parameters of flounder were significantly decreased. Metabolomic and transcriptomic analyses of liver tissue showed obvious difference about biological pathways and identified biomarkers (around 2502 genes and 16 secondary metabolites). Those significantly differentially expressed genes (DEGs) and their enriched pathways were mainly related to immune response, oxidative stress, lipids metabolism, glycometabolism, amino acid and nucleotide metabolism and regulation of protein processes, while those identified secondary metabolites were mainly enriched in tryptophan metabolism, biosynthesis of unsaturated fatty acids, linoleic acid metabolism and glutathione metabolism. Additionally, multi-omic method was used to explore response mechanisms of key pathways under MeHg stress. In this regard, only 57 DEGs and 6 secondary metabolites were significantly enriched in 7 pathways to constitute an integrated regulatory network, including glutathione metabolism, thyroid hormone synthesis, linoleic acid metabolism, biosynthesis of unsaturated fatty acids, tryptophan metabolism pathway, serotonergic synapse and African trypanosomiasis. Above all, we could speculate that antioxidative function, lipids metabolism, nervous system and amino acid metabolism were the more sensitive targets in response to MeHg stress, which were conductive to deeply understand the response mechanisms of fish at ELSs under MeHg exposure. Those identified biomarkers could also be widely used for toxicological studies of pollutants and ecological risks monitoring.</p

Transforming Cancer-Associated Fibroblast Barrier into Drug Depots to Boost Chemo-Immunotherapy in “Shooting Fish in a Barrel” Pattern

The cancer-associated fibroblast (CAF) barrier in pancreatic ductal adenocarcinoma (PDAC) greatly restricts clinical outcomes. Major obstacles to PDAC treatment include restricted immune cell infiltration and drug penetration and the immunosuppressive microenvironment. Here, we reported a “shooting fish in a barrel” strategy by preparing a lipid–polymer hybrid drug delivery system (PI/JGC/L-A) that could overcome the CAF barrier by turning it into a “barrel” with antitumor drug depot properties to alleviate the immunosuppressive microenvironment and increase immune cell infiltration. PI/JGC/L-A is composed of a pIL-12-loaded polymeric core (PI) and a JQ1 and gemcitabine elaidate coloaded liposomal shell (JGC/L-A) that has the ability to stimulate exosome secretion. By normalizing the CAF barrier to create a CAF “barrel” with JQ1, stimulating the secretion of gemcitabine-loaded exosomes from the CAF “barrel” to the deep tumor site, and leveraging the CAF “barrel” to secrete IL-12, PI/JGC/L-A realized effective drug delivery to the deep tumor site, activated antitumor immunity at the tumor site, and produced significant antitumor effects. In summary, our strategy of transforming the CAF barrier into antitumor drug depots represents a promising strategy against PDAC and might benefit the treatment of any tumors facing a drug delivery barrier